ES2226378T3 - PROCEDURE FOR SYNTHESIS OF COX-2 INHIBITORS. - Google Patents
PROCEDURE FOR SYNTHESIS OF COX-2 INHIBITORS.Info
- Publication number
- ES2226378T3 ES2226378T3 ES99918706T ES99918706T ES2226378T3 ES 2226378 T3 ES2226378 T3 ES 2226378T3 ES 99918706 T ES99918706 T ES 99918706T ES 99918706 T ES99918706 T ES 99918706T ES 2226378 T3 ES2226378 T3 ES 2226378T3
- Authority
- ES
- Spain
- Prior art keywords
- alkyl
- procedure
- accordance
- aryl
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/02—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups
- C07C251/30—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having nitrogen atoms of imino groups quaternised
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Virology (AREA)
- Oncology (AREA)
- Engineering & Computer Science (AREA)
- Communicable Diseases (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Molecular Biology (AREA)
- Pain & Pain Management (AREA)
- Pulmonology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Un procedimiento para la síntesis de un compuesto de fórmula I: en la que: están presentes de 0-2 grupos R; cada R, R¿ y R¿ representan independientemente alquilo C1-10, arilo C6-10, aralquilo, halo, -S(O)mH, - S(O)malquilo C1-6, -S(O)marilo, nitro, amino, alquilamino C1-6, dialquilamino C1-6, -S(O)mNH2, -S(O)mNH-alquilo C1- 6, -S(O)mNHC(O)CF3 y ciano, los grupos alquilo y arilo, y las porciones alquilo y arilo del aralquilo, -S(O)malquilo C1-6, -S(O)marilo, alquilamino C1-6, dialquilamino C1-6 y -S(O)mNH-alquilo C1-6 estando opcionalmente sustituidos con 1-3 grupos seleccionados entre alquilo C1-4, arilo, halo, hidroxilo, -S(O)mH, -S(O)malquilo C1-6, -CN, alcoxi C1-6, amino, alquilamino C1-6, dialquilamino C1-6, -S(O)mNH2, -S(O)mNH- alquilo C1-6, -S(O)mNHC(O)CF3 y ariloxi; Y es C o N; y m es 0, 1 ó 2, que comprende hacer reaccionar de un compuesto de fórmula II: en la que de R2 a R5 representan independientemente alquilo C1-6, arilo o aralquilo, y X- representa un contraión adecuado, con un compuesto de fórmula III: en la que R, R¿ e Y son como se define previamente, en presencia de una base para producir un compuesto de fórmula I.A process for the synthesis of a compound of formula I: in which: 0-2 R groups are present; each R, R ¿and R ¿independently represent C1-10 alkyl, C6-10 aryl, aralkyl, halo, -S (O) mH, - S (O) C1-6 alkyl, -S (O) maryl, nitro, amino, C1-6 alkylamino, C1-6 dialkylamino, -S (O) mNH2, -S (O) mNH-C1-6 alkyl, -S (O) mNHC (O) CF3 and cyano, alkyl and aryl groups, and the alkyl and aryl portions of the aralkyl, -S (O) C1-6 alkyl, -S (O) maryl, C1-6 alkylamino, C1-6 dialkylamino and -S (O) mNH-C1-6 alkyl being optionally substituted with 1-3 groups selected from C1-4 alkyl, aryl, halo, hydroxyl, -S (O) mH, -S (O) C1-6 alkyl, -CN, C1-6 alkoxy, amino, C1-6 alkylamino, C1-6 dialkylamino, -S (O) mNH2, -S (O) mNH- C1-6 alkyl, -S (O) mNHC (O) CF3 and aryloxy; Y is C or N; and m is 0, 1 or 2, which comprises reacting a compound of formula II: wherein from R2 to R5 independently represent C1-6 alkyl, aryl or aralkyl, and X- represents a suitable counterion, with a compound of formula III: in which R, R ¿and Y are as previously defined, in the presence of a base to produce a compound of formula I.
Description
Procedimiento para la síntesis de inhibidores de COX-2.Procedure for the synthesis of inhibitors of COX-2
La presente invención se refiere a un procedimiento para la síntesis de ciertos compuestos que inhiben la COX-2. Adicionalmente se incluyen ciertos compuestos intermedios.The present invention relates to a procedure for the synthesis of certain compounds that inhibit the COX-2 Additionally certain compounds are included intermediate
La ciclooxigenasa-2 (COX-2) es una enzima que está implicada en el dolor, la inflamación, las contracciones uterinas inducidas por hormonas y ciertos tipos de crecimiento de cánceres. Hasta hace poco, solamente se había caracterizado una forma de la ciclooxigenasa, la correspondiente a la ciclooxigenasa-1 o enzima constitutiva, como se identificó originalmente en vesículas seminales bovinas. Recientemente se ha clonado, secuenciado y caracterizado a partir de fuentes gallináceas, murinas y humanas el gen para una segunda forma inducible de ciclooxigenasa (ciclooxigenasa-2). Esta enzima es distinta de la ciclooxigenasa-1. La COX-2 es rápida y fácilmente inducible por un número de agentes entre los que se incluyen mitógenos, endotoxinas, hormonas, citoquinas y factores de crecimiento. Mientras que la enzima constitutiva, la ciclooxigenasa-1, es responsable, en gran parte, de la liberación basal endógena de prostaglandinas y por tanto es importante en sus funciones fisiológicas tales como el mantenimiento de la integridad gastrointestinal y el flujo sanguíneo renal, la forma inducible, la ciclooxigenasa-2, es responsable principalmente de los efectos patológicos de las prostaglandinas donde se produzca la inducción rápida de la enzima en respuesta a dichos agentes tales como agentes inflamatorios, hormonas, factores de crecimiento, y citoquinas. Así, un inhibidor selectivo de la ciclooxigenasa-2 reducirá la fiebre, inhibirá el proceso inflamatorio, contrarrestará las contracciones uterinas inducidas por hormonas y tendrá efectos anticancerígenos potenciales, junto con una capacidad mermada para inducir algunos de los efectos secundarios basados en el mecanismo.Cyclooxygenase-2 (COX-2) is an enzyme that is involved in the pain, inflammation, uterine contractions induced by hormones and certain types of cancer growth. Until little, only one form of the cyclooxygenase, the one corresponding to the cyclooxygenase-1 or constitutive enzyme, as originally identified in bovine seminal vesicles. Recently it has been cloned, sequenced and characterized from Gallinaceous, murine and human sources the gene for a second form inducible cyclooxygenase (cyclooxygenase-2). This Enzyme is distinct from cyclooxygenase-1. The COX-2 is quickly and easily inducible by a number of agents including mitogens, endotoxins, hormones, cytokines and growth factors. While the constitutive enzyme, cyclooxygenase-1, is responsible, in large part, for the endogenous basal release of prostaglandins and therefore it is important in its functions physiological such as maintaining integrity gastrointestinal and renal blood flow, inducible form, the cyclooxygenase-2, is primarily responsible for the pathological effects of prostaglandins where the rapid induction of the enzyme in response to such agents as inflammatory agents, hormones, growth factors, and cytokines Thus, a selective inhibitor of cyclooxygenase-2 will reduce fever, inhibit inflammatory process, will counteract uterine contractions hormone induced and will have anticancer effects potentials, along with a diminished ability to induce some of Side effects based on the mechanism.
Petrich y colaboradores, Heterocycles, 39 (2), 1994, 623-637 describen sales de vinamidinio, por ejemplo el compuesto 2 del Esquema 1 cuando Y = H y el compuesto 7 del Esquema 4. Sales de vinamidinio adicionales se describen como los compuestos 14a, 14d, 14f, 14g y 14k en Bacher y colaboradores, Z. Naturforsch., B: Chem. Sci. 44 (7), 1981, 839-849, también como los compuestos 5a-5d en Andris Liepa, Aust. J. Chem., 34, 1981, 2647-2655 y como el compuesto 2 en Reichardt y Halbritter, Liebigs Ann. Chem., 3, 1975, 470-483. En el documento WO-A-9.006.913 (Hoechst Aktiengesellschaft) se describe un procedimiento general para la preparación de sales de arilvinamidinio.Petrich et al., Heterocycles, 39 (2), 1994, 623-637 describe vinamidinium salts, by example compound 2 of Scheme 1 when Y = H and compound 7 of Scheme 4. Additional vinamidinium salts are described as compounds 14a, 14d, 14f, 14g and 14k in Bacher et al., Z. Naturforsch., B: Chem. Sci. 44 (7), 1981, 839-849, also as the compounds 5th-5th in Andris Liepa, Aust. J. Chem., 34, 1981, 2647-2655 and as compound 2 in Reichardt and Halbritter, Liebigs Ann. Chem., 3, 1975, 470-483. In WO-A-9.006.913 (Hoechst Aktiengesellschaft) describes a general procedure for the preparation of aryl vinamidinium salts.
Los compuestos preparados en la presente solicitud en los que R es halo, alquiltio C_{1-6}, ciano, alquilo C_{1-6}, fluoroalquilo C_{1-6}, o -C(R^{4})(R^{5})OH en la que R^{4} y R^{5} son hidrógeno o alquilo C_{1-6}; R' es fenilo sustituido en la posición 4 por SO_{2}CH_{3}, SO_{2}NH_{2}SO_{2}, NHC(O)CF_{3} o SO_{2}NHCH_{3}; y R'' es halo, alquiltio C_{1-6}, ciano, alquilo C_{1-6}, fluoroalquilo C_{1-6}, o -C(R^{8})(R^{9})OH en la que R^{8} y R^{9} son hidrógeno o alquilo C_{1-6}, nitro o NR^{11}R^{12} en la que R^{11} y R^{12} son hidrógeno o alquilo C_{1-6}; se describen en el documento WO-A-9.803.484 (Merck Frosst Canada Inc.).The compounds prepared herein application in which R is halo, C 1-6 alkylthio, cyano, C 1-6 alkyl, fluoroalkyl C 1-6, or -C (R 4) (R 5) OH in which R 4 and R 5 are hydrogen or alkyl C 1-6; R 'is phenyl substituted at position 4 by SO 2 CH 3, SO 2 NH 2 SO 2, NHC (O) CF 3 or SO 2 NHCH 3; and R '' is halo, C 1-6 alkylthio, cyano, alkyl C 1-6, C 1-6 fluoroalkyl, or -C (R 8) (R 9) OH where R 8 and R 9 they are hydrogen or C 1-6 alkyl, nitro or NR 11 R 12 in which R 11 and R 12 are hydrogen or C 1-6 alkyl; are described in the document WO-A-9,803,484 (Merck Frosst Canada Inc.).
Un objeto de la presente invención es proporcionar un esquema de síntesis para compuestos que inhiben la COX-2 que utiliza temperaturas reducidas en la síntesis.An object of the present invention is provide a synthesis scheme for compounds that inhibit COX-2 that uses reduced temperatures in the synthesis.
Otro objeto de la presente invención es utilizar una ruta sintética que proporciona altos rendimientos.Another object of the present invention is to use a synthetic route that provides high yields.
Otro objeto de la presente invención es proporcionar un esquema de síntesis que utiliza un procedimiento con el mínimo de etapas.Another object of the present invention is provide a synthesis scheme that uses a procedure with The minimum stages.
Estos y otros objetos serán evidentes para aquellos con conocimientos ordinarios en la materia a partir de las enseñanzas contenidas en el presente documento.These and other objects will be apparent to those with ordinary knowledge in the field from the teachings contained in this document.
Se describe un procedimiento para la síntesis de un compuesto de fórmula I:A procedure for the synthesis of a compound of formula I:
en la que:in the that:
están presentes de 0-2 grupos R;are present of 0-2 groups R;
cada R, R' y R'' representan independientemente
alquilo C_{1-10}, arilo
C_{6-10}, aralquilo, halo,
-S(O)_{m}H, -S(O)_{m}alquilo
C_{1-6}, -S(O)_{m}arilo, nitro,
amino, alquilamino C_{1-6}, dialquilamino
C_{1-6}, -S(O)_{m}NH_{2},
-S(O)_{m}NH-alquilo
C_{1-6}, -S(O)_{m}
NHC(O)CF_{3} y ciano,each R, R 'and R''independently represent C 1-10 alkyl, C 6-10 aryl, aralkyl, halo, -S (O) m H, -S (O) m C 1-6 alkyl, -S (O) m aryl, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino, -S (O) m NH_ {2}, -S (O) m NH-C 1-6 alkyl, -S (O) m
NHC (O) CF 3 and cyano,
los grupos alquilo y arilo, y las porciones alquilo y arilo del aralquilo, -S(O)_{m}alquilo C_{1-6}, -S(O)_{m}arilo, alquilamino C_{1-6}, dialquilamino C_{1-6} y -S(O)_{m}NH-alquilo C_{1-6} estando opcionalmente sustituidos con 1-3 grupos seleccionados entre alquilo C_{1-4}, arilo, halo, hidroxilo, -S(O)_{m}H, -S(O)_{m}alquilo C_{1-6}, -CN, alcoxi C_{1-6}, amino, alquilamino C_{1-6}, dialquilamino C_{1-6}, -S(O)_{m}NH_{2}, -S(O)_{m}NH-alquilo C_{1-6}, -S(O)_{m}NHC(O)CF_{3} y ariloxi;the alkyl and aryl groups, and the portions alkyl and aryl of the aralkyl, -S (O) m alkyl C 1-6, -S (O) m aryl, C 1-6 alkylamino, dialkylamino C_ {1-6} and -S (O) m NH-alkyl C 1-6 being optionally substituted with 1-3 groups selected from alkyl C 1-4, aryl, halo, hydroxyl, -S (O) m H, -S (O) m alkyl C 1-6, -CN, C 1-6 alkoxy, amino, C 1-6 alkylamino, dialkylamino C 1-6, -S (O) m NH 2, -S (O) m NH-alkyl C_ {1-6}, -S (O) m NHC (O) CF 3 and aryloxy;
Y es C o N;Y is C or N;
y m es 0, 1 ó 2,and m is 0, 1 or 2,
que comprende la reacción de un compuesto de fórmula II:which comprises the reaction of a compound of formula II:
en la que R^{2} hasta R^{5} representan independientemente alquilo C_{1-6}, arilo o aralquilo, y X^{-} representa un contraión adecuado,in which R 2 to R 5 independently represent C 1-6 alkyl, aryl or aralkyl, and X - represents a counterion suitable,
con un compuesto de fórmula III:with a compound of formula III:
en la que R, R' e Y son como se define previamente,in which R, R 'and Y are as define previously,
en presencia de una base para producir un compuesto de fórmula I.in the presence of a base for produce a compound of formula I.
También se incluye el compuesto intermedio hexafluorofosfato de 2-cloro-1,3-bis(dimetil amino)-trietinio.The intermediate compound is also included hexafluorophosphate 2-chloro-1,3-bis (dimethyl amino) -trietinium.
La invención se describe en detalle usando los términos definidos a continuación, a menos que se especifique lo contrario.The invention is described in detail using the terms defined below, unless specified contrary.
El término "alquilo" se refiere a un radical derivado de un alcano monovalente (hidrocarburo) que contiene entre 1 y 15 átomos de carbono a menos que se defina lo contrario. Puede ser lineal, ramificado o cíclico. Los grupos alquilo lineales o ramificados preferidos incluyen metilo, etilo, propilo, isopropilo, butilo y t-butilo. Los grupos cicloalquilo preferidos incluyen ciclopentilo y ciclohexilo.The term "alkyl" refers to a radical derived from a monovalent alkane (hydrocarbon) containing between 1 and 15 carbon atoms unless otherwise defined. It can be linear, branched or cyclic. Preferred linear or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t -butyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.
Alquilo también incluye un grupo alquilo lineal o ramificado que contiene o está interrumpido por una porción cicloalquileno. Los ejemplos incluyen los siguientes:Alkyl also includes a linear alkyl group or branched that contains or is interrupted by a portion cycloalkylene. Examples include the following:
en la que: x + y = entre 0-10 y w + z = entre 0-9.in which: x + y = between 0-10 and w + z = between 0-9.
El alquileno y la porción(es) alquilo monovalente del grupo alquilo pueden estar unidos a cualquier punto de unión disponible para la porción cicloalquileno.The alkylene and the alkyl portion (s) monovalent of the alkyl group may be attached to any point Binding available for the cycloalkylene portion.
Cuando está presente un alquilo sustituido, esto se refiere a un grupo alquilo lineal, ramificado o cíclico como se define anteriormente, sustituido con 1-3 grupos como se define con respecto a cada variable.When a substituted alkyl is present, this refers to a linear, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as It is defined with respect to each variable.
El término "alcoxi" se refiere a aquellos grupos de la longitud designada en cualquiera de las dos configuraciones lineal o ramificada. Ejemplos de dichos grupos alcoxi son metoxi, etoxi, propoxi, isopropoxi, butoxi, isobutoxi, t-butoxi, pentoxi, isopentoxi, hexoxi, isohexoxi y similares.The term "alkoxy" refers to those groups of the designated length in either linear or branched configuration. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t -butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
El término "halógeno" se pretende que incluya flúor, cloro, bromo y yodo.The term "halogen" is intended to include fluorine, chlorine, bromine and iodine.
Arilo se refiere a anillos aromáticos por ejemplo, fenilo, fenilo sustituido y grupos similares así como anillos que están fusionados, por ejemplo, naftilo. Arilo contiene así al menos un anillo que tiene al menos 6 átomos, estando presentes hasta dos de dichos anillos, que contienen hasta 10 átomos, con dobles enlaces alternados (resonantes) entre los átomos de carbono adyacentes. Los grupos arilo preferidos son fenilo y naftilo. Los arilos sustituidos preferidos incluyen fenilo y naftilo sustituidos con uno o dos grupos.Aryl refers to aromatic rings by example, phenyl, substituted phenyl and similar groups as well as rings that are fused, for example, naphthyl. Arilo contains thus at least one ring that has at least 6 atoms, being present up to two of said rings, containing up to 10 atoms, with alternating (resonant) double bonds between atoms adjacent carbon. Preferred aryl groups are phenyl and Naphthyl Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
X^{-} representa un contraión adecuado. Por lo tanto, los intermedios de fórmula II son sales que pueden o no ser "farmacéuticamente aceptables" como se define a continuación. Un subconjunto de valores de X^{-} que es de particular interés incluye los siguientes: fosfonatos, por ejemplo, hexafluorofosfato y similares; sulfatos; sulfonatos, por ejemplo, mesilato, tosilato, triflato y similares; acetatos, por ejemplo, trifluoroacetato y similares; perclorato; borato, por ejemplo, tetrafluoroborato, tetrafenilborato y similares; antimonato, por ejemplo, hexafluoroantimonato; haluros, por ejemplo, Cl, F, Br y I; benzoato y napsilato.X - represents a suitable counterion. For the therefore, the intermediates of formula II are salts that may or may not be "pharmaceutically acceptable" as defined below. A subset of values of X - which is of particular interest includes the following: phosphonates, for example, hexafluorophosphate and Similar; sulfates; sulfonates, for example, mesylate, tosylate, triflate and the like; acetates, for example, trifluoroacetate and Similar; perchlorate; borate, for example, tetrafluoroborate, tetraphenylborate and the like; antimony, for example, hexafluoroantimonate; halides, for example, Cl, F, Br and I; benzoate and napsilate.
Los valores preferidos de X^{-} que se usan en el procedimiento descrito en el presente documento se seleccionan del grupo compuesto por: hexafluorofosfato; los haluros, sulfato; los sulfonatos; trifluoroacetato; perclorato; tetrafluoroborato; tetrafenilborato y hexafluoroantimonato.Preferred values of X - which are used in the procedure described in this document are selected from the group consisting of: hexafluorophosphate; halides, sulfate; the sulphonates; trifluoroacetate; perchlorate; tetrafluoroborate; tetraphenylborate and hexafluoroantimonate.
Las sales englobadas dentro del término "sales farmacéuticamente aceptables" se refieren a sales sustancialmente no tóxicas de los compuestos que se preparan generalmente mediante la reacción de la base libre con un ácido orgánico o inorgánico adecuado. Entre las sales representativas se incluyen las siguientes: acetato, benzoato, los haluros; napsilato y fosfato/difosfato.Salts encompassed within the term "salts pharmaceutically acceptable "refer to salts substantially non-toxic compounds that are generally prepared by the reaction of the free base with an organic or inorganic acid suitable. Representative salts include the following: acetate, benzoate, halides; napsilate and phosphate / diphosphate.
Los compuestos usados como materiales de partida en la presente invención pueden contener uno o más átomos de carbono asimétricos y pueden existir en formas ópticamente activas y racémicas. Todos estos compuestos son útiles dentro del alcance de la presente invención. Cuando un compuesto es quiral, los enantiómeros separados, sustancialmente libre del otro, se incluyen junto con las mezclas de enantiómeros. También se incluyen los polimorfos e hidratos de los compuestos.The compounds used as starting materials in the present invention may contain one or more carbon atoms asymmetric and can exist in optically active forms and racemic All these compounds are useful within the scope of The present invention. When a compound is chiral, the separate enantiomers, substantially free of each other, are included together with the enantiomer mixtures. Also included are polymorphs and hydrates of the compounds.
Los compuestos de fórmula I preparados mediante el procedimiento reivindicado se pueden administrar en formas de dosificación oral tales como comprimidos, cápsulas (cada una incluyendo formulaciones de liberación sostenida y liberación regulada), píldoras, polvos, gránulos, elixires, tinturas, suspensiones, jarabes y emulsiones. Además, también se pueden administrar parenteralmente, por ejemplo, mediante inyección intravenosa (tanto bolo como infusión), intraperitoneal, subcutánea o intramuscular.The compounds of formula I prepared by The claimed process can be administered in the form of oral dosage such as tablets, capsules (each including sustained release and release formulations regulated), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. In addition, you can also administer parenterally, for example, by injection intravenous (both bolus and infusion), intraperitoneal, subcutaneous or intramuscular.
En un aspecto de la invención, se describe un procedimiento para la síntesis de un compuesto de fórmula I:In one aspect of the invention, a procedure for the synthesis of a compound of formula I:
en la que:in the that:
están presentes de 0-2 grupos R;are present of 0-2 groups R;
cada R, R' y R'' representan independientemente
alquilo C_{1-10}, arilo
C_{6-10}, aralquilo, halo,
-S(O)_{m}H, -S(O)_{m}alquilo
C_{1-6}, -S(O)_{m}arilo, nitro,
amino, alquilamino C_{1-6}, dialquilamino
C_{1-6}, -S(O)_{m}NH_{2},
-S(O)_{m}NH-alquilo
C_{1-6}, -S(O)_{m}
NHC(O)CF_{3} y ciano,each R, R 'and R''independently represent C 1-10 alkyl, C 6-10 aryl, aralkyl, halo, -S (O) m H, -S (O) m C 1-6 alkyl, -S (O) m aryl, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino, -S (O) m NH_ {2}, -S (O) m NH-C 1-6 alkyl, -S (O) m
NHC (O) CF 3 and cyano,
los grupos alquilo y arilo, y las porciones alquilo y arilo del aralquilo, -S(O)_{m}alquilo C_{1-6}, -S(O)_{m}arilo, alquilamino C_{1-6}, dialquilamino C_{1-6} y -S(O)_{m}NH-alquilo C_{1-6} estando opcionalmente sustituidos con 1-3 grupos seleccionados entre alquilo C_{1-4}, arilo, halo, hidroxilo, -S(O)_{m}H, -S(O)_{m}alquilo C_{1-6}, -CN, alcoxi C_{1-6}, amino, alquilamino C_{1-6}, dialquilamino C_{1-6}, -S(O)_{m}NH_{2}, -S(O)_{m}NH-alquilo C_{1-6}, -S(O)_{m}NHC(O)CF_{3} y ariloxi;the alkyl and aryl groups, and the portions alkyl and aryl of the aralkyl, -S (O) m alkyl C 1-6, -S (O) m aryl, C 1-6 alkylamino, dialkylamino C_ {1-6} and -S (O) m NH-alkyl C 1-6 being optionally substituted with 1-3 groups selected from alkyl C 1-4, aryl, halo, hydroxyl, -S (O) m H, -S (O) m alkyl C 1-6, -CN, C 1-6 alkoxy, amino, C 1-6 alkylamino, dialkylamino C 1-6, -S (O) m NH 2, -S (O) m NH-alkyl C_ {1-6}, -S (O) m NHC (O) CF 3 and aryloxy;
Y es C o N;Y is C or N;
y m es 0, 1 ó 2,and m is 0, 1 or 2,
que comprende la reacción de un compuesto de fórmula II:which comprises the reaction of a compound of formula II:
en la que R^{2} hasta R^{5} representan independientemente alquilo C_{1-6}, arilo o aralquilo, y X^{-} representa un contraión adecuado,in which R 2 to R 5 independently represent C 1-6 alkyl, aryl or aralkyl, and X - represents a counterion suitable,
con un compuesto de fórmula III:with a compound of formula III:
en la que R, R' e Y son como se define previamente,in which R, R 'and Y are as define previously,
en presencia de una base para producir un compuesto de fórmula I.in the presence of a base for produce a compound of formula I.
En un aspecto preferido de la invención, se describe un procedimiento para la síntesis de un compuesto de fórmula I':In a preferred aspect of the invention, describes a procedure for the synthesis of a compound of formula I ':
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
en la que:in the that:
están presentes de 0-2 grupos R;are present of 0-2 groups R;
cada R, R' y R'' representan independientemente
alquilo C_{1-10}, arilo
C_{6-10}, aralquilo, halo,
-S(O)_{m}H, -S(O)_{m}alquilo
C_{1-6}, -S(O)_{m}arilo, nitro,
amino, alquilamino C_{1-6}, dialquilamino
C_{1-6}, -S(O)_{m}NH_{2},
-S(O)_{m}NH-alquilo
C_{1-6}, -S(O)_{m}
NHC(O)CF_{3} y ciano,each R, R 'and R''independently represent C 1-10 alkyl, C 6-10 aryl, aralkyl, halo, -S (O) m H, -S (O) m C 1-6 alkyl, -S (O) m aryl, nitro, amino, C 1-6 alkylamino, C 1-6 dialkylamino, -S (O) m NH_ {2}, -S (O) m NH-C 1-6 alkyl, -S (O) m
NHC (O) CF 3 and cyano,
los grupos alquilo y arilo, y las porciones alquilo y arilo del aralquilo, -S(O)_{m}alquilo C_{1-6}, -S(O)_{m}arilo, alquilamino C_{1-6}, dialquilamino C_{1-6} y -S(O)_{m}NH-alquilo C_{1-6} estando opcionalmente sustituidos con 1-3 grupos seleccionados entre alquilo C_{1-4}, arilo, halo, hidroxilo, -S(O)_{m}H, -S(O)_{m}alquilo C_{1-6}, -CN, alcoxi C_{1-6}, amino, alquilamino C_{1-6}, dialquilamino C_{1-6}, -S(O)_{m}NH_{2}, -S(O)_{m}NH-alquilo C_{1-6}, -S(O)_{m}NHC(O)CF_{3} y ariloxi;the alkyl and aryl groups, and the portions alkyl and aryl of the aralkyl, -S (O) m alkyl C 1-6, -S (O) m aryl, C 1-6 alkylamino, dialkylamino C_ {1-6} and -S (O) m NH-alkyl C 1-6 being optionally substituted with 1-3 groups selected from alkyl C 1-4, aryl, halo, hydroxyl, -S (O) m H, -S (O) m alkyl C 1-6, -CN, C 1-6 alkoxy, amino, C 1-6 alkylamino, dialkylamino C 1-6, -S (O) m NH 2, -S (O) m NH-alkyl C_ {1-6}, -S (O) m NHC (O) CF 3 and aryloxy;
Y es C o N;Y is C or N;
y m es 0, 1 ó 2,and m is 0, 1 or 2,
que comprende la reacción de un compuesto de fórmula II:which comprises the reaction of a compound of formula II:
en la que R^{2} hasta R^{5} representan independientemente alquilo C_{1-6}, arilo o aralquilo, y X^{-} representa un contraión adecuado,in which R 2 to R 5 independently represent C 1-6 alkyl, aryl or aralkyl, and X - represents a counterion suitable,
con un compuesto de fórmula III:with a compound of formula III:
en la que R, R' e Y son como se define previamente,in which R, R 'and Y are as define previously,
en presencia de una base para producir un compuesto de fórmula I'.in the presence of a base for produce a compound of formula I '.
Un aspecto de la invención que es de interés particular se refiere a los procedimientos descritos anteriormente, en los que está presente un grupo R y es alquilo C_{1-10}, arilo C_{6-10}, aralquilo, halo, -S(O)_{m}H, -S(O)_{m}alquilo C_{1-6}, -S(O)_{m} aralquilo, -S(O)_{m}arilo, nitro o ciano.An aspect of the invention that is of interest particular refers to the procedures described above, in which a group R is present and is alkyl C 1-10, aryl C 6-10, aralkyl, halo, -S (O) m H, -S (O) m C 1-6 alkyl, -S (O) m aralkyl, -S (O) m aryl, nitro or cyano.
Más particularmente, los procedimientos que son de interés particular se refieren al procedimiento descrito anteriormente en el que está presente un R y representa un grupo alquilo C_{1-10}. Incluso más particularmente, el procedimiento se refiere al procedimiento descrito anteriormente en el que está presente un R que representa un metilo. Lo más preferido es el procedimiento que se describe anteriormente en el que está presente un R y representa un metilo unido de la siguiente manera:More particularly, the procedures that are of particular interest refer to the procedure described previously in which an R is present and represents a group C 1-10 alkyl. Even more particularly, the procedure refers to the procedure described above in which is present an R representing a methyl. Most preferred it is the procedure described above in which it is present an R and represents a attached methyl of the following way:
Dentro de este subconjunto, todas las otras variables son como se definió originalmente.Within this subset, all others Variables are as originally defined.
En otro aspecto, la invención engloba un procedimiento para la fabricación de un compuesto de fórmula I en la que Y representa N. Dentro de este subconjunto, todas las otras variables son como se definió originalmente.In another aspect, the invention encompasses a process for the manufacture of a compound of formula I in the which Y represents N. Within this subset, all others Variables are as originally defined.
En otro aspecto de la invención que es de interés particular, el procedimiento engloba un compuesto en el que R' se selecciona del grupo compuesto por: arilo C_{6-10} sustituido con -S(O)_{m}-alquilo C_{1-6}. Más particularmente, el procedimiento engloba un compuesto en el que R' representa un fenilo sustituido con metanosulfonilo en la posición 4' como se muestra a continuación:In another aspect of the invention that is of interest In particular, the process encompasses a compound in which R 'is Select from the group consisting of: C6-10 aryl substituted with -S (O) m -alkyl C_ {1-6}. More particularly, the procedure encompasses a compound in which R 'represents a substituted phenyl with methanesulfonyl in the 4 'position as shown at continuation:
Dentro de este subconjunto, todas las otras variables son como se definió anteriormente.Within this subset, all others Variables are as defined above.
En otro aspecto de la invención que es de interés particular, el procedimiento engloba un compuesto en el que R'' se selecciona entre alquilo C_{1-10}, arilo C_{6-10}, aralquilo, halo, -S(O)_{m}H, -S(O)_{m}alquilo C_{1-6}, nitro y ciano. Más particularmente, la invención que es de interés se refiere a un procedimiento en el que R'' es halo o arilo C_{6-10}. Incluso más particularmente, R'' representa halo, especialmente cloro. Dentro de este subconjunto, todas las otras variables son como se definió originalmente.In another aspect of the invention that is of interest In particular, the process encompasses a compound in which R '' is select from C 1-10 alkyl, aryl C 6-10, aralkyl, halo, -S (O) m H, -S (O) m alkyl C 1-6, nitro and cyano. More particularly, the invention that is of interest refers to a process in which R '' is halo or C 6-10 aryl. Even more particularly, R '' represents halo, especially chlorine. Within this subset, all other variables are as defined originally.
En otro aspecto de la invención, el procedimiento utiliza un compuesto de fórmula II en el que R^{2} hasta R^{5} representan alquilo C_{1-6}, y en particular, metilo. Dentro de este subconjunto, todas las otras variables son como se definió originalmente.In another aspect of the invention, the process uses a compound of formula II in which R 2 to R 5 represent C 1-6 alkyl, and in particular, methyl. Within this subset, all other variables are as originally defined.
En otro aspecto de la invención, el procedimiento utiliza un compuesto de fórmula II en la que X^{-} representa un miembro seleccionado del grupo compuesto por: hexafluorofosfato, haluro, sulfato, sulfonato, borato, trifluoroacetato o perclorato. Más particularmente X^{-} representa un miembro seleccionado del grupo compuesto por: hexafluorofosfato, cloruro, un sulfonato seleccionado entre metanosulfonato, toluensulfonato y trifluorometilsulfonato, tetrafluoroborato o trifluoroacetato. Dentro de este subconjunto, todas las otras variables son como se definió originalmente.In another aspect of the invention, the process uses a compound of formula II in which X - represents a member selected from the group consisting of: hexafluorophosphate, halide, sulfate, sulphonate, borate, trifluoroacetate or perchlorate. More particularly X - represents a member selected from the group consisting of: hexafluorophosphate, chloride, a sulphonate selected from methanesulfonate, toluenesulfonate and trifluoromethylsulfonate, tetrafluoroborate or trifluoroacetate. Within this subset, all other variables are as originally defined.
Como se usa en el presente documento, el término "base" se refiere a bases orgánicas e inorgánicas, tales como hidróxido de sodio o de potasio, carbonato de cesio, bases de alcóxidos de Li, Na o K, tales como isopropóxido de litio, sodio o potasio, t-butóxido de litio, sodio o potasio y similares, bases de amidas de Li, Na o K, tales como LHMDS, LDA y similares, y bases de hidruros de Li, Na o K.As used herein, the term "base" refers to organic and inorganic bases, such as sodium or potassium hydroxide, cesium carbonate, Li, Na or K alkoxide bases, such as lithium isopropoxide, sodium or potassium, lithium t- butoxide, sodium or potassium and the like, amide bases of Li, Na or K, such as LHMDS, LDA and the like, and hydride bases of Li, Na or K.
Para los propósitos de esta memoria descriptiva, las reacciones, a menos que se especifique lo contrario, generalmente se llevan a cabo en un disolvente tal como benceno, clorobenceno, diclorobenceno, tolueno y xileno; disolventes etéreos tales como dietil éter, di-n-butil y diisopentil éteres, anisol, éteres cíclicos tales como tetrahidropirano, 4-metil-1,3-dioxano, dihidropirano, tetrahidrofurfurilo, metil éter, etil éter, 2-etoxitetrahidrofurano y tetrahidrofurano (THF); disolventes halocarbonados incluyendo mono o dihalo alquilos C_{1-4} tales como diclorometano; disolventes hidrocarbonados lineales, ramificados o cíclicos C_{6-10} incluyendo hexano; y disolventes que contienen nitrógeno incluyendo N,N-dimetilacetamida, N,N-dimetilformamida (DMF), N-etilpirrolidinona, N-metilpirrolidinona, y acetonitrilo. Los disolventes preferibles son alcohol, THF y DMF.For the purposes of this specification, reactions, unless otherwise specified, they are usually carried out in a solvent such as benzene, chlorobenzene, dichlorobenzene, toluene and xylene; ethereal solvents such as diethyl ether, di-n-butyl and diisopentyl ethers, anisole, cyclic ethers such as tetrahydropyran, 4-methyl-1,3-dioxane, dihydropyran, tetrahydrofurfuryl, methyl ether, ethyl ether, 2-ethoxytetrahydrofuran and tetrahydrofuran (THF); halocarbon solvents including mono or dihalo alkyls C 1-4 such as dichloromethane; solvents linear, branched or cyclic hydrocarbons C 6-10 including hexane; and solvents that contain nitrogen including N, N-dimethylacetamide, N, N-dimethylformamide (DMF), N-ethylpyrrolidinone, N-methylpyrrolidinone, and acetonitrile. The Preferred solvents are alcohol, THF and DMF.
Normalmente la reacción se lleva a cabo en un disolvente sustancialmente no reactivo, por ejemplo, tetrahidrofurano, dioxano, alcanol C_{1-6}, clorobenceno, diclorobenceno o xileno.Normally the reaction is carried out in a substantially non-reactive solvent, for example, tetrahydrofuran, dioxane, C 1-6 alkanol, chlorobenzene, dichlorobenzene or xylene.
La reacción se puede llevar a cabo de manera sorprendente a temperatura sustancialmente ambiente.The reaction can be carried out in a manner surprising at substantially room temperature.
Los compuestos de fórmula I son útiles para el alivio del dolor, la fiebre y la inflamación de una variedad de dolencias que incluyen fiebre reumática, síntomas asociados a la gripe y otras infecciones víricas, catarro, dolor lumbar y del cuello, dismenorrea, dolor de cabeza, dolor de muelas, esguinces y distensiones, miositis, neuralgia, sinovitis, artritis, incluyendo artritis reumatoide, enfermedades degenerativas de las articulaciones (osteoartritis), gota y espondilitis anquilosante, bursitis, quemaduras, lesiones, procedimientos post quirúrgicos y dentales. Además, dicho compuesto puede inhibir las transformaciones neoplásicas celulares y el crecimiento de tumores metastáticos y por lo tanto se puede usar en el tratamiento del cáncer.The compounds of formula I are useful for relief of pain, fever and inflammation of a variety of medical conditions that include rheumatic fever, symptoms associated with influenza and other viral infections, cold, low back pain and neck, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative diseases of the joints (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, post surgical procedures and Dental In addition, said compound can inhibit transformations. Cellular neoplastic and growth of metastatic tumors and by Therefore it can be used in cancer treatment.
Los compuestos de fórmula I también pueden ser útiles para el tratamiento de la demencia incluyendo demencia pre-senil y senil, y en particular, la demencia asociada con la enfermedad de Alzheimer (es decir, la demencia de Alzheimer).The compounds of formula I can also be useful for the treatment of dementia including dementia pre-senile and senile, and in particular, dementia associated with Alzheimer's disease (i.e. dementia of Alzheimer's)
En virtud de su alta actividad ciclooxigenasa-2 (COX-2) y/o su selectividad para la ciclooxigenasa-2 sobre la ciclooxigenasa-1 (COX-1), los compuestos de fórmula I son útiles como una alternativa a otros fármacos antiinflamatorios no esteroideos (AINES) particularmente cuando dichos fármacos antiinflamatorios no esteroideos pueden estar contraindicados en pacientes con úlceras pépticas, gastritis, enteritis regional, colitis ulcerativa, diverticulitis o con un historial de lesiones gastrointestinales recurrentes; sangrado gastrointestinal, trastornos de la coagulación incluyendo anemia tal como hipoprotrombinemia, hemofilia u otros problemas de sangrado (incluyendo aquellos relacionados con una función plaquetaria deteriorada o reducida); enfermedades del riñón (por ejemplo, función renal deteriorada); aquellos previos a cirugía o a la toma de anticoagulantes; y aquellos susceptibles de asma inducido por AINES.By virtue of its high activity cyclooxygenase-2 (COX-2) and / or its selectivity for cyclooxygenase-2 over cyclooxygenase-1 (COX-1), the compounds of formula I are useful as an alternative to others non-steroidal anti-inflammatory drugs (NSAIDs) particularly when said non-steroidal anti-inflammatory drugs may be contraindicated in patients with peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis or with a history of recurrent gastrointestinal lesions; bleeding gastrointestinal, bleeding disorders including anemia such such as hypoprothrombinemia, hemophilia or other bleeding problems (including those related to a platelet function impaired or reduced); kidney diseases (for example, impaired renal function); those before surgery or taking of anticoagulants; and those susceptible to asthma induced by NSAIDs
Los compuestos son inhibidores de la ciclooxigenasa-2 y por lo tanto son útiles en el tratamiento de enfermedades mediadas por ciclooxigenasa-2 tales como las enumeradas anteriormente. Esta actividad se ilustra por su capacidad para inhibir selectivamente la ciclooxigenasa-2 sobre la ciclooxigenasa-1. Por consiguiente, en un ensayo, la capacidad de los compuestos de esta invención para tratar enfermedades mediadas por ciclooxigenasa se puede demostrar midiendo la cantidad de prostaglandina E_{2} (PGE_{2}) sintetizada en presencia de ácido araquidónico, ciclooxigenasa-1 o ciclooxigenasa-2 y un compuesto de fórmula I. Los valores CI_{50} representan la concentración de inhibidor necesaria para restituir la síntesis de PGE_{2} al 50% de aquella obtenida en comparación con el control no inhibido.The compounds are inhibitors of cyclooxygenase-2 and therefore are useful in the treatment of diseases mediated by cyclooxygenase-2 such as those listed previously. This activity is illustrated by its ability to selectively inhibit cyclooxygenase-2 on the cyclooxygenase-1. Therefore, in one trial, the ability of the compounds of this invention to treat Cyclooxygenase-mediated diseases can be demonstrated by measuring the amount of prostaglandin E2 (PGE2) synthesized in presence of arachidonic acid, cyclooxygenase-1 or cyclooxygenase-2 and a compound of formula I. IC 50 values represent the inhibitor concentration necessary to restore the synthesis of PGE2 to 50% of that obtained compared to the uninhibited control.
Para el tratamiento de cualquiera de estas enfermedades mediadas por ciclooxigenasa, los compuestos de fórmula I se pueden administrar oral, tópica, parenteral, rectalmente o por inhalación de un pulverizador en formulaciones de dosificación unitaria que contienen vehículos, adyuvantes y transportadores no tóxicos convencionales farmacéuticamente aceptables. El término parenteral como se usa en esta invención incluye inyecciones subcutáneas, intravenosas, intramusculares, intrasternales o técnicas de infusión. Además del tratamiento de animales de sangre caliente tales como ratones, ratas, caballos, ganado ovino, perros, gatos, etc. el compuesto de la invención es eficaz en el tratamiento de humanos.For the treatment of any of these cyclooxygenase-mediated diseases, the compounds of formula I can be administered orally, topically, parenterally, rectally or by inhalation of a sprayer in dosage formulations unit containing vehicles, adjuvants and transporters not conventional toxic pharmaceutically acceptable. The term parenteral as used in this invention includes injections subcutaneous, intravenous, intramuscular, intrasternal or infusion techniques In addition to the treatment of blood animals hot such as mice, rats, horses, sheep, dogs, cats, etc. the compound of the invention is effective in the treatment of humans.
El procedimiento se describe en profundidad junto con el siguiente esquema.The procedure is described in depth together With the following scheme.
Esquema IScheme I
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
\dotable{\tabskip\tabcolsep#\hfil\+#\hfil\tabskip0ptplus1fil\dddarstrut\cr}{
1. \+ Base\cr 2. \+ Ácido\cr 3. \+
Amoniaco\cr}\ dotable {\ tabskip \ tabcolsep # \ hfil \ + # \ hfil \ tabskip0ptplus1fil \ dddarstrut \ cr} {
1. \ + Base \ cr 2. \ + Acid \ cr 3. \ +
Ammonia \ cr}
El procedimiento descrito en esta invención se puede describir junto con la descripción genérica anterior. Se preparó el reactivo de Grignard a (0,1-3 M, 0,8-2 equivalentes) a partir del haluro correspondiente, por ejemplo, Z es igual a cloruro, y magnesio en disolvente adecuado, tal como THF, éter, tolueno o sus mezclas. El reactivo de Grignard se añadió a una disolución fría (0 a -78ºC, preferentemente -10 a -30ºC) de la amida b en un disolvente adecuado, conduciendo a la formación de la cetona III. La cetona III se aisló después de la eliminación acuosa por extracción y cristalización.The procedure described in this invention can be described together with the generic description above. The Grignard reagent at (0.1-3 M, 0.8-2 equivalents) was prepared from the corresponding halide, for example, Z is equal to chloride, and magnesium in suitable solvent, such as THF, ether, toluene or their mixtures. The Grignard reagent was added to a cold solution (0 to -78 ° C, preferably -10 to -30 ° C) of the amide b in a suitable solvent, leading to the formation of ketone III. Ketone III was isolated after aqueous removal by extraction and crystallization.
El tratamiento de la cetona III (0,05-2 M) con una base adecuada, por ejemplo, un alcoxilo metálico, en un disolvente adecuado de -78ºC aproximadamente a 50ºC aproximadamente, normalmente por debajo de 20ºC aproximadamente, produce la formación de un intermedio enolato (no mostrado). El enolato se hace reaccionar con la sal de trimetinio para formar un compuesto intermedio (no mostrado) que se inactiva en un ácido adecuado (0,05-10 M). Un ejemplo es el ácido acético.The ketone III treatment (0.05-2 M) with a suitable base, for example, a metal alkoxy, in a suitable solvent of -78 ° C at about 50 ° C, usually below Approximately 20 ° C, produces the formation of an enolate intermediate (not shown). The enolato is reacted with the salt of trimetinium to form an intermediate compound (not shown) that is inactive in a suitable acid (0.05-10 M). A example is acetic acid.
Se añadió amoniaco a la muestra (normalmente en forma de disolución acuosa) y la mezcla se mantuvo entre temperatura ambiente y temperatura de reflujo durante varias horas. El producto se aisló por extracción usando, por ejemplo, éter, acetato de etilo o cloruro de metileno y cristalización para formar un compuesto de fórmula I.Ammonia was added to the sample (usually in aqueous solution form) and the mixture was kept between temperature ambient and reflux temperature for several hours. The product was isolated by extraction using, for example, ether, ethyl acetate or methylene chloride and crystallization to form a compound of formula I.
La invención se ilustra en profundidad mediante los siguientes ejemplos no limitantes en los que, a menos que se indique lo contrario:The invention is illustrated in depth by the following non-limiting examples in which, unless indicate otherwise:
(i) todas las operaciones se llevaron a cabo a
temperatura ambiente o de laboratorio, esto es, a una temperatura en
el intervalo de 18-25ºC aproximadamente; la
evaporación del disolvente se llevó a cabo en condiciones de presión
reducida (600-4000 Pascales: 4,5-30
mm de Hg) con una temperatura del baño de hasta 60ºC
aproximadamente; el transcurso de las reacciones se siguió mediante
cromatografía de capa fina (TLC) o cromatografía líquida de alta
presión (HPLC) y los tiempos de reacción se dan solamente a modo de
ilustración; el polimorfismo puede resultar en el aislamiento de
materiales con diferentes puntos de fusión en algunas preparaciones;
la estructura y la pureza de todos los productos finales se aseguró
mediante al menos una de las siguientes técnicas: TLC,
espectrometría de masas, espectrometría de resonancia magnética
nuclear (RMN) o datos microanalíticos; cuando se dan, los datos de
RMN están en forma de valores delta (\delta) para el diagnóstico
de los protones principales, dados en partes por millón (ppm) en
relación al tetrametilsilano (TMS) como patrón interno, determinado
a 300 MHz o 400 MHz usando el disolvente indicado; las abreviaturas
convencionales usadas para las formas de las señales son: s,
singlete; d, doblete; t, triplete; m, multiplete; a, ancho; etc.;
además "Ar" significa una señal aromática; los símbolos
químicos tienen sus significados habituales; también se usan las
siguientes abreviaturas: v (volumen), p (peso), p.e. (punto de
ebullición), p.f. (punto de fusión), L (litro(s)), mL
(mililitros), g (gramo(s)), mg (miligramo(s)), mol
(moles), mmol (milimoles), eq (equivalen-
te(s)).(i) all operations were carried out at room or laboratory temperature, that is, at a temperature in the range of approximately 18-25 ° C; evaporation of the solvent was carried out under conditions of reduced pressure (600-4000 Pascals: 4.5-30 mm Hg) with a bath temperature of up to approximately 60 ° C; the course of the reactions was followed by thin layer chromatography (TLC) or high pressure liquid chromatography (HPLC) and the reaction times are given by way of illustration only; Polymorphism can result in the isolation of materials with different melting points in some preparations; the structure and purity of all final products was ensured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance spectrometry (NMR) or microanalytical data; when given, the NMR data are in the form of delta (δ) values for the diagnosis of the main protons, given in parts per million (ppm) in relation to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; The conventional abbreviations used for the signal forms are: s, singlet; d, double up; t, triplet; m, multiplet; a, width; etc.; in addition "Ar" means an aromatic signal; chemical symbols have their usual meanings; The following abbreviations are also used: v (volume), p (weight), eg (boiling point), pf (melting point), L (liter (s)), mL (milliliters), g (gram (s) ), mg (milligram (s)), mol (moles), mmol (millimoles), eq (equivalent)
te (s)).
Ejemplo de preparación 1Preparation Example one
Una disolución de metil 6-metilnicotinato (21,56 g), y N,O-dimetilhidroxiamina (13,9 g) en THF (150 mL) se enfrió a -10ºC. Se añadió cloruro de isopropilmagnesio (110 mL) durante 2,5 h. La mezcla de reacción se echó en ácido acético acuoso (10% en vol, 126 mL) a 5ºC. Se añadió tolueno (60 mL) a la mezcla, y a continuación se separaron las fases. La fase acuosa se extrajo con tolueno (2 x 60 mL) y se eliminó el disolvente. Las impurezas sólidas se eliminaron por filtración y el filtrado se concentró para dar la amida de Weinreb PE-1 en forma de un aceite naranja pálido (24,2 g).A solution of methyl 6-methylnicotinate (21.56 g), and N, O- dimethylhydroxyamine (13.9 g) in THF (150 mL) was cooled to -10 ° C. Isopropylmagnesium chloride (110 mL) was added for 2.5 h. The reaction mixture was poured into aqueous acetic acid (10% vol, 126 mL) at 5 ° C. Toluene (60 mL) was added to the mixture, and then the phases were separated. The aqueous phase was extracted with toluene (2 x 60 mL) and the solvent was removed. Solid impurities were removed by filtration and the filtrate was concentrated to give Weinreb PE-1 amide as a pale orange oil (24.2 g).
Ejemplo de preparación 2Preparation Example 2
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Se cargó una mezcla de magnesio (191 g, 7,86 mol), tolueno (4 L), cloruro de 4-tiometilbencilo (566 g, 3,28 mol) y tetrahidrofurano (0,545 L, 6,73 mol) durante 3-4 horas. Se cargó un matraz adicional con la amida de Weinreb PE-1 (300 g, 1,66 mol) y tolueno (1,7 L) y se enfrió a -20ºC. La disolución de Grignard preparada anteriormente se añadió durante 30 minutos y la mezcla se conservó durante 1 hora. La mezcla de reacción se inactivó mediante la adición de ácido acético acuoso al 50% (0,5 L). Se añadió tolueno (1 L) y agua (1 L) y se separaron las fases. La fase acuosa se extrajo con tolueno (2 x 2 L). La mezcla de extractos orgánicos se extrajo con ácido clorhídrico diluido (1 x 2 L). Se añadió acetato de etilo a la fase acuosa y el pH se ajustó con amoniaco (0,6 L). Las fases se separaron y la fase acuosa se extrajo con acetato de etilo (2 x 1,25 L). La mezcla de extractos se concentró en un rotoevaporador para dar PE-2 en forma de un sólido amarillo pálido (326,5 g).A mixture of magnesium was loaded (191 g, 7.86 mol), toluene (4 L), 4-thiomethylbenzyl chloride (566 g, 3.28 mol) and tetrahydrofuran (0.545 L, 6.73 mol) for 3-4 hours An additional flask was charged with the amide Weinreb PE-1 (300 g, 1.66 mol) and toluene (1.7 L) and cooled to -20 ° C. Grignard's solution prepared previously it was added for 30 minutes and the mixture was preserved for 1 hour. The reaction mixture was quenched by addition of 50% aqueous acetic acid (0.5 L). Toluene (1 was added L) and water (1 L) and the phases were separated. The aqueous phase was extracted with toluene (2 x 2 L). The organic extract mixture was extracted with dilute hydrochloric acid (1 x 2 L). Ethyl acetate was added to the aqueous phase and the pH was adjusted with ammonia (0.6 L). Phases they were separated and the aqueous phase was extracted with ethyl acetate (2 x 1.25 L). The extract mixture was concentrated in a rotary evaporator to give PE-2 in the form of a pale yellow solid (326.5 g).
Ejemplo de preparación 3Preparation Example 3
Una mezcla de cetosulfuro PE-2 (270 g, 1,05 mol), ácido sulfúrico (2 N) (20 mL), y metanol (2,70 L) se calentó a 55ºC. Se añadió una disolución acuosa de wolframato sódico (6,0 g, 0,02 mol), y a continuación se añadió peróxido de hidrógeno (380 mL) durante 1 hora. Se añadió agua (3 L) y la mezcla se enfrió a temperatura ambiente, y a continuación se filtró. Los sólidos se lavaron con agua (2 L) y se secaron sobre vacío con una corriente de nitrógeno para dar la cetosulfona PE-3 (250,2 g) en forma de un sólido incoloro.A mixture of ketosulfide PE-2 (270 g, 1.05 mol), sulfuric acid (2 N) (20 mL), and methanol (2.70 L) It was heated to 55 ° C. An aqueous solution of wolfram was added sodium (6.0 g, 0.02 mol), and then peroxide of hydrogen (380 mL) for 1 hour. Water (3 L) and the mixture were added It was cooled to room temperature, and then filtered. The solids were washed with water (2 L) and dried under vacuum with a nitrogen stream to give the ketosulfone PE-3 (250.2 g) in the form of a colorless solid.
\vskip1.000000\baselineskip\ vskip1.000000 \ baselineskip
Se añadió ácido cloroacético (0,99 kg, 10,57 mmol) a dimetilformamida (4,37 kg, 59,78 mol) y la mezcla se calentó a 75ºC. Se añadió oxicloruro de fósforo (3,36 kg, 21,91 mol) durante 5 horas. La mezcla de reacción se mantuvo durante 3 horas, y a continuación se enfrió a temperatura ambiente. Se añadió concurrentemente la mezcla de reacción y el hidróxido sódico (19,7 kg) durante 2 horas a una mezcla de agua (12 kg), ácido hexafluorofosfórico acuoso al 60% en peso (2,87 kg, 11,71 mol) e hidróxido sódico 4,7 N (2,3 kg) a < 9ºC. El matraz de reacción se lavó con dimetilformamida (0,36 kg) y se añadió para la inactivación. La mezcla se mantuvo durante 40 minutos y a continuación se filtró. El sólido en bruto se lavó con agua (8,6 kg). El sólido se recristalizó en agua (10,8 kg) e isopropanol (3,8 kg) calentando a 67ºC. La mezcla se enfrió a 4ºC y a continuación se filtró. El sólido se lavó con agua/isopropanol (11 kg, 26:1) y se secó para dar el compuesto objetivo 1 en forma de un sólido amarillo (2,28 kg).Chloroacetic acid (0.99 kg, 10.57 mmol) was added to dimethylformamide (4.37 kg, 59.78 mol) and the mixture was heated to 75 ° C. Phosphorus oxychloride (3.36 kg, 21.91 mol) was added over 5 hours. The reaction mixture was maintained for 3 hours, and then cooled to room temperature. The reaction mixture and sodium hydroxide (19.7 kg) were added concurrently for 2 hours to a mixture of water (12 kg), 60% by weight aqueous hexafluorophosphoric acid (2.87 kg, 11.71 mol) and 4.7 N sodium hydroxide (2.3 kg) at <9 ° C. The reaction flask was washed with dimethylformamide (0.36 kg) and added for inactivation. The mixture was maintained for 40 minutes and then filtered. The crude solid was washed with water (8.6 kg). The solid was recrystallized from water (10.8 kg) and isopropanol (3.8 kg) by heating at 67 ° C. The mixture was cooled to 4 ° C and then filtered. The solid was washed with water / isopropanol (11 kg, 26: 1) and dried to give objective compound 1 as a yellow solid (2.28 kg).
A una suspensión de un compuesto 1-a (1,5 kg, 5,12 mol) en THF (10 L) se añadió butóxido potásico (617 g, 5,5 mol) en THF (5,38 L, 5,38 mol) a < 15ºC. Se añadió el compuesto 1 (1,65 kg, 4,6 mol) y la mezcla de reacción se mantuvo a temperatura ambiente. La mezcla de reacción se transfirió a una disolución de ácido acético (2,0 L) en THF (5 L) y la mezcla se agitó durante 1 h. Se añadió hidróxido de amonio acuoso concentrado (4 L) y la mezcla se calentó a reflujo durante 3 horas. La mezcla se enfrió a 22ºC y se separaron las fases. La fase orgánica se concentró hasta 3 L y se añadió acetato de isopropilo (5 L). La disolución resultante se concentró de nuevo hasta 3-4 L y se añadió acetato de isopropilo (19 L). La disolución se lavó con bicarbonato sódico saturado (2 x 9,5 L) y agua (2 x 9,5 L), se concentró hasta sequedad y se purificó para dar el compuesto 2 en forma de sólido (1,65 kg).To a suspension of a 1- a compound (1.5 kg, 5.12 mol) in THF (10 L) was added potassium butoxide (617 g, 5.5 mol) in THF (5.38 L, 5.38 mol) at <15 ° C. Compound 1 (1.65 kg, 4.6 mol) was added and the reaction mixture was maintained at room temperature. The reaction mixture was transferred to a solution of acetic acid (2.0 L) in THF (5 L) and the mixture was stirred for 1 h. Concentrated aqueous ammonium hydroxide (4 L) was added and the mixture was heated at reflux for 3 hours. The mixture was cooled to 22 ° C and the phases were separated. The organic phase was concentrated to 3 L and isopropyl acetate (5 L) was added. The resulting solution was concentrated again to 3-4 L and isopropyl acetate (19 L) was added. The solution was washed with saturated sodium bicarbonate (2 x 9.5 L) and water (2 x 9.5 L), concentrated to dryness and purified to give compound 2 as a solid (1.65 kg).
Se añadió cloruro de cloroacetilo (14,50 g, 0,112 mol) a dimetilformamida (50 mL) y la mezcla se calentó a 75ºC para dar una disolución amarilla clara. Se añadió oxicloruro de fósforo (18,9 g, 0,123 mol) a 5 mL/h. La mezcla de reacción se mantuvo durante 3 horas y a continuación se enfrió a temperatura ambiente. Se añadió concurrentemente la mezcla de reacción y el hidróxido sódico 5 N (70 mL) durante 1 hora a una mezcla de agua (200 mL) y hexafluorofosfato sódico (21 g, 0,125 mol) a < 9ºC. El matraz de reacción se lavó con dimetilformamida (2 mL) y se añadió para la inactivación. La mezcla se mantuvo durante 40 minutos y a continuación se filtró.Chloroacetyl Chloride (14.50 g, 0.121 was added mol) to dimethylformamide (50 mL) and the mixture was heated to 75 ° C to give a light yellow solution. Phosphorus oxychloride was added (18.9 g, 0.123 mol) at 5 mL / h. The reaction mixture was maintained. for 3 hours and then cooled to room temperature. The reaction mixture and the hydroxide were added concurrently 5 N sodium (70 mL) for 1 hour at a mixture of water (200 mL) and sodium hexafluorophosphate (21 g, 0.125 mol) at <9 ° C. The flask of reaction was washed with dimethylformamide (2 mL) and added for inactivation The mixture was maintained for 40 minutes and at then leaked.
El sólido en bruto se lavó con agua (100 mL). El sólido se recristalizó en agua (224 mL) e isopropanol (56 mL) calentando a 70ºC. La mezcla se enfrió a 4ºC y a continuación se filtró. El sólido se lavó con agua/isopropanol (100 mL, 20:1) y se secó para dar CDT-fosfato en forma de un sólido amarillo claro (26,8 g).The crude solid was washed with water (100 mL). He solid was recrystallized from water (224 mL) and isopropanol (56 mL) heating at 70 ° C. The mixture was cooled to 4 ° C and then filter. The solid was washed with water / isopropanol (100 mL, 20: 1) and was dried to give CDT-phosphate as a solid light yellow (26.8 g).
Claims (24)
alquilo C_{1-6}.8. A process according to claim 1 wherein R 'represents a C 6-10 aryl substituted with -S (O) m
C 1-6 alkyl.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US8288898P | 1998-04-24 | 1998-04-24 | |
| US82888P | 1998-04-24 | ||
| US8566898P | 1998-05-15 | 1998-05-15 | |
| US85668P | 1998-05-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2226378T3 true ES2226378T3 (en) | 2005-03-16 |
Family
ID=26767964
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES99918706T Expired - Lifetime ES2226378T3 (en) | 1998-04-24 | 1999-04-20 | PROCEDURE FOR SYNTHESIS OF COX-2 INHIBITORS. |
Country Status (28)
| Country | Link |
|---|---|
| US (2) | US6040319A (en) |
| EP (1) | EP1071745B1 (en) |
| JP (2) | JP3325264B2 (en) |
| KR (1) | KR100414998B1 (en) |
| CN (1) | CN1178658C (en) |
| AR (1) | AR015279A1 (en) |
| AT (1) | ATE272613T1 (en) |
| AU (1) | AU759469B2 (en) |
| BR (2) | BR9909844B1 (en) |
| CA (1) | CA2329193C (en) |
| CZ (1) | CZ292515B6 (en) |
| DE (1) | DE69919151T2 (en) |
| DK (1) | DK1071745T3 (en) |
| EA (1) | EA002975B1 (en) |
| ES (1) | ES2226378T3 (en) |
| HK (1) | HK1031399A1 (en) |
| HR (1) | HRP20000722B1 (en) |
| HU (1) | HU227627B1 (en) |
| IL (2) | IL139127A0 (en) |
| NZ (1) | NZ507597A (en) |
| PL (1) | PL193248B1 (en) |
| PT (1) | PT1071745E (en) |
| RS (1) | RS49945B (en) |
| SI (1) | SI1071745T1 (en) |
| SK (1) | SK284805B6 (en) |
| TW (1) | TW474934B (en) |
| UA (1) | UA57143C2 (en) |
| WO (1) | WO1999055830A2 (en) |
Families Citing this family (38)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5861419A (en) | 1996-07-18 | 1999-01-19 | Merck Frosst Canad, Inc. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| CA2485739C (en) * | 1999-01-14 | 2009-09-22 | Lonza Ag | Process for preparing 1-(6-methylpyridin-3-yl)-2-[(4-(methylsulphonyl)phenyl]ethanone |
| MXPA01007169A (en) | 1999-01-14 | 2003-06-06 | Lonza Ag | 1-(6- methylpyridine- 3-yl)-2-[4- (methylsulfonyl) phenyl] ethanone and method for its preparation. |
| JP2001115963A (en) | 1999-10-13 | 2001-04-27 | Daikin Ind Ltd | Compressor |
| US6858631B1 (en) | 1999-11-29 | 2005-02-22 | Merck & Co., Inc. | Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6′-methyl-[2,3′]bipyridinyl |
| DK1248618T3 (en) | 1999-11-29 | 2006-07-10 | Merck Frosst Canada Inc | Polymorphic, amorphous and hydrated forms of 5-chloro-3- (4-methanesulfonylphenyl) -6'-methyl- [2,3 '] bipyridinyl |
| AU784490B2 (en) * | 1999-12-08 | 2006-04-13 | Pharmacia Corporation | Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect |
| JP2001261653A (en) * | 2000-03-17 | 2001-09-26 | Sankio Chemical Co Ltd | Method for synthesizing pyridine derivative |
| US6521642B2 (en) | 2000-05-26 | 2003-02-18 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6′-methyl-[2,3′]bipyridinyl in pure crystalline form and process for synthesis |
| PH12001001175B1 (en) * | 2000-05-26 | 2006-08-10 | Merck Sharp & Dohme | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl- (2,3')bipyridinyl in pure crystalline form and process for synthesis |
| US6800647B2 (en) | 2000-05-26 | 2004-10-05 | Merck & Co., Inc. | 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3]bipyridinyl in pure crystalline form and process for synthesis |
| PE20020146A1 (en) * | 2000-07-13 | 2002-03-31 | Upjohn Co | OPHTHALMIC FORMULATION INCLUDING A CYCLOOXYGENASE-2 (COX-2) INHIBITOR |
| AU5754701A (en) * | 2000-07-13 | 2002-01-30 | Pharmacia Corp | Method of using cox-2 inhibitors in the treatment and prevention of ocular cox-2mediated disorders |
| US7115565B2 (en) * | 2001-01-18 | 2006-10-03 | Pharmacia & Upjohn Company | Chemotherapeutic microemulsion compositions of paclitaxel with improved oral bioavailability |
| MY137736A (en) | 2001-04-03 | 2009-03-31 | Pharmacia Corp | Reconstitutable parenteral composition |
| WO2002089798A2 (en) * | 2001-05-04 | 2002-11-14 | Merck & Co., Inc. | Method and compositions for treating migraines |
| UA80682C2 (en) * | 2001-08-06 | 2007-10-25 | Pharmacia Corp | Orally deliverable stabilized oral suspension formulation and process for the incresaing physical stability of thixotropic pharmaceutical composition |
| JP4700916B2 (en) | 2004-02-02 | 2011-06-15 | 富士フイルムファインケミカルズ株式会社 | Method for producing pyridine derivative |
| US7271383B2 (en) * | 2004-08-11 | 2007-09-18 | Lexmark International, Inc. | Scanning system with feedback for a MEMS oscillating scanner |
| EP1784179A4 (en) | 2004-08-24 | 2010-03-31 | Merck Sharp & Dohme | Combination therapy for treating cyclooxygenase-2 mediated diseases or conditions in patients at risk of thrombotic cardiovascular events |
| CN101626787A (en) * | 2007-01-19 | 2010-01-13 | 马林克罗特公司 | Diagnostic and therapeutic cyclooxygenase-2 binding ligands |
| PT2479166E (en) | 2009-02-27 | 2014-11-28 | Cadila Healthcare Ltd | A process for the preparation of etoricoxib |
| ES2683125T3 (en) | 2010-06-16 | 2018-09-25 | Glenmark Generics Limited | Process for the preparation of 2,3-diaryl-5-substituted pyridines and their intermediates |
| WO2012066570A2 (en) | 2010-11-15 | 2012-05-24 | Virdev Intermediates Pvt. Ltd. | A process for cyclooxygenase-2 selective inhibitor |
| ITMI20110362A1 (en) | 2011-03-09 | 2012-09-10 | F I S Fabbrica Italiana Sint P A | PROCEDURE FOR THE PREPARATION OF 1- (6-METHYLPYRIDIN-3-IL) -2- [4- (METHYLSOLFONYL) PHENYL] ETHANONE, AN INTERMEDIATE OF THE ETHORICOXIB. |
| EP2714676B1 (en) | 2011-05-27 | 2019-04-24 | Farma GRS, d.o.o. | A process for the preparation of polymorphic form i of etoricoxib |
| ITMI20111455A1 (en) | 2011-07-29 | 2013-01-30 | Italiana Sint Spa | NEW PROCEDURE FOR THE PREPARATION OF 1- (6-METHYLPYRIDIN-3-IL) -2- [4- (METHYLSOLFONYL) PHENYL] ETHANONE, AN INTERMEDIATE OF THE ETHORICOXIB. |
| CN103204803A (en) | 2012-01-13 | 2013-07-17 | 阿尔弗雷德·E·蒂芬巴赫尔有限责任两合公司 | Method used for synthesizing etoricoxib |
| ITMI20120394A1 (en) * | 2012-03-14 | 2013-09-15 | Zach System Spa | SYNTHESIS PROCESS OF A DERIVED KETOSOLFONE |
| WO2013144977A2 (en) | 2012-03-30 | 2013-10-03 | Mylan Laboratories Ltd. | An improved process for the preparation of etoricoxib |
| GR1007973B (en) * | 2012-06-26 | 2013-09-12 | Φαρματεν Αβεε, | Novel n-oxyiminium compounds as intermediates of an improved process for the preparation of 2,3-diaryl-5-substituted pyridines |
| PL2887924T3 (en) | 2012-08-27 | 2017-09-29 | Cadila Healthcare Limited | Pharmaceutical compositions of etoricoxib |
| ITVI20130014A1 (en) | 2013-01-22 | 2014-07-23 | Italiana Sint Spa | VERY EFFICIENT PROCEDURE TO PREPARE AN ETORICOXIB INTERMEDIATE |
| WO2014114352A1 (en) * | 2013-01-25 | 2014-07-31 | Synthon Bv | Process for making etoricoxib |
| CN104418799A (en) * | 2013-09-03 | 2015-03-18 | 天津药物研究院 | Etoricoxib crystal as well as preparation method and application thereof |
| WO2015036550A1 (en) | 2013-09-13 | 2015-03-19 | Synthon B.V. | Process for making etoricoxib |
| US10500178B2 (en) | 2015-03-13 | 2019-12-10 | The Board Of Trustees Of The Leland Stanford Junior University | LTB4 inhibition to prevent and treat human lymphedema |
| CN104817473A (en) * | 2015-03-27 | 2015-08-05 | 南京大学 | Application of 1-dimethylamino-3-dimethylimino-2-chloropropene perchlorate in preparation of Etocoxib |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA988522A (en) * | 1972-05-05 | 1976-05-04 | Haydn W.R. Williams | 1,8-naphthyridine compounds |
| DE3842062A1 (en) * | 1988-12-14 | 1990-06-28 | Hoechst Ag | EXPLOSION-SAFE 1-DIMETHYLAMINO-3-DIMETHYLIMINO-2-ARYLPROPEN-1 SALTS, METHOD FOR THEIR PRODUCTION AND THEIR USE |
| US5861419A (en) * | 1996-07-18 | 1999-01-19 | Merck Frosst Canad, Inc. | Substituted pyridines as selective cyclooxygenase-2 inhibitors |
| SK283261B6 (en) * | 1996-07-18 | 2003-04-01 | Merck Frosst Canada & Co. / Merck Frosst Canada & Cie. | Substituted pyridines, pharmaceutical composition containing them and use |
-
1999
- 1999-04-20 AT AT99918706T patent/ATE272613T1/en active
- 1999-04-20 DE DE69919151T patent/DE69919151T2/en not_active Expired - Lifetime
- 1999-04-20 SI SI9930632T patent/SI1071745T1/en unknown
- 1999-04-20 JP JP2000545976A patent/JP3325264B2/en not_active Expired - Lifetime
- 1999-04-20 SK SK1589-2000A patent/SK284805B6/en not_active IP Right Cessation
- 1999-04-20 RS YUP-641/00A patent/RS49945B/en unknown
- 1999-04-20 UA UA2000116652A patent/UA57143C2/en unknown
- 1999-04-20 NZ NZ507597A patent/NZ507597A/en not_active IP Right Cessation
- 1999-04-20 AU AU36557/99A patent/AU759469B2/en not_active Expired
- 1999-04-20 WO PCT/US1999/008645 patent/WO1999055830A2/en active IP Right Grant
- 1999-04-20 PL PL344108A patent/PL193248B1/en unknown
- 1999-04-20 CA CA002329193A patent/CA2329193C/en not_active Expired - Lifetime
- 1999-04-20 PT PT99918706T patent/PT1071745E/en unknown
- 1999-04-20 BR BRPI9909844-0A patent/BR9909844B1/en not_active IP Right Cessation
- 1999-04-20 CN CNB998075507A patent/CN1178658C/en not_active Expired - Lifetime
- 1999-04-20 EP EP99918706A patent/EP1071745B1/en not_active Expired - Lifetime
- 1999-04-20 ES ES99918706T patent/ES2226378T3/en not_active Expired - Lifetime
- 1999-04-20 EA EA200001102A patent/EA002975B1/en not_active IP Right Cessation
- 1999-04-20 DK DK99918706T patent/DK1071745T3/en active
- 1999-04-20 KR KR10-2000-7011764A patent/KR100414998B1/en active Protection Beyond IP Right Term
- 1999-04-20 CZ CZ20003940A patent/CZ292515B6/en not_active IP Right Cessation
- 1999-04-20 BR BRPI9917739A patent/BRPI9917739B8/en not_active IP Right Cessation
- 1999-04-20 HU HU0101407A patent/HU227627B1/en unknown
- 1999-04-20 IL IL13912799A patent/IL139127A0/en active IP Right Grant
- 1999-04-23 US US09/298,127 patent/US6040319A/en not_active Expired - Lifetime
- 1999-04-23 AR ARP990101884A patent/AR015279A1/en active IP Right Grant
- 1999-04-23 TW TW088106545A patent/TW474934B/en active
-
2000
- 2000-01-21 US US09/488,774 patent/US6252116B1/en not_active Expired - Fee Related
- 2000-10-18 IL IL139127A patent/IL139127A/en not_active IP Right Cessation
- 2000-10-24 HR HR20000722A patent/HRP20000722B1/en not_active IP Right Cessation
-
2001
- 2001-03-26 HK HK01102195A patent/HK1031399A1/en not_active IP Right Cessation
-
2002
- 2002-05-22 JP JP2002147700A patent/JP3834263B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2226378T3 (en) | PROCEDURE FOR SYNTHESIS OF COX-2 INHIBITORS. | |
| US6369275B1 (en) | Process for making diaryl pyridines useful as cox-2 inhibitors | |
| US5585504A (en) | Process of making cox-2 inhibitors having a lactone bridge | |
| JP4157325B2 (en) | Process for producing diarylpyridines useful as inhibitors of COX-2 | |
| JP2013047245A (en) | Method for preparing pyridine derivative | |
| ES2223128T3 (en) | MANUFACTURING PROCEDURE OF 2-ARIL-3-ARIL-5-HALOPIRIDINES USED AS COX-2 INHIBITORS. | |
| AU2013280925A1 (en) | Production of N-substituted sulfoximine pyridine N-oxides | |
| JPH04243875A (en) | Process for producing 2-phenyl-6-(pyrimidin-2- yl)pyridine compound, intermediate compound and process for producing intermediate compound | |
| JP7489390B2 (en) | Preparation of sulfonamide herbicide process intermediates | |
| MXPA00010438A (en) | Process for synthesizing cox-2 inhibitors | |
| GB1579541A (en) | Process for the production of (1,1 - dithien - (3)-yl - 1 - hydroxy - (3) - propyl) - (1-phenyl - 1 - hydroxy - (2) - propyl)-amine and (1,1 - dithien - (3) - yl-(1) - propen - (3) - yl) - (1 - phenyl-1 - hydroxy - (2) - propyl)- amine | |
| JPS63179862A (en) | Production of hydroxy-substituted heterocyclic compound |